Periodontitis is a chronic inflammation and destruction of periodontal tissue, leading to alveolar bone loss induced by osteoclasts (OCs). c-Kit receptor tyrosine kinase is localized on OC surface whereas the legend for c-Kit or Kit legend (KL) is expressed in osteoblasts. Two naturally occurring isoforms of c-Kit, which differ in the presence or absence of four amino acids, have dramatic differences in activation of particular signal transduction. Soluble KL (s-KL) acts indirectly to stimulate OC formation and activity in vitro. Mice that produce only s-KL develop an early osteopenia that becomes more severe as animals mature. The negative bone balance in these mice is due primarily to the increased OC number, indicating a role of c-Kit signaling in the regulation of bone turnover. Ligand-induced downregulation of receptor tyrosine kinases, representing a balance between degradation and recycling to cell membrane, constitutes a major determinant of signaling potency of the receptors. The activated KL/c-Kit complex induces phosphorylation and stimulation of proto- oncoprotein Cbl which subsequently down-regulates the receptor through E3 ubiquitin ligase activity. c-Cbl targets activated tyrosine kinase receptors for ubiquitination and degradation in OCs. Mice that express an ubiquitination-deficient c-Cbl with a point mutation (C379A) in the RING domain (c-Cbl A/-) have increased number of OC and develop osteopenia. In addition, homozygous and heterozygous mutants have darker coats, feet and tails than wild type or c-Cbl-/- mice, consistent with possibly increased activity of c-Kit in these mice. However, the precise mechanism by which c-Cbl modulates c-Kit expression and signaling in OCs remain to be defined. We hypothesize that the absence of c-Cbl ubiquitin ligase activity leads to sustained activation of c-Kit signaling, resulting in the defects observed I. Our specific aims are: 1) characterize the role of c-Kit in the regulation of OC function and cytoskeletal organization, specifically focusing on the roles of the two c-Kit isoforms on OC functions;and 2) characterize the effect of c-Cbl-dependent ubiquitination in c-Kit down-regulation on OC functions. PUBLIC HEALTH RELEVANCE: Periodontitis is one of the most chronic diseases afflicting the quality of life;it is bacterially mediated inflammation that induces alveolar bone loss. The improved understanding of the c-Kit signaling and its function in the regulation of osteoclastogenesis will provide new insights into OC biology and may lead to a novel target for therapeutic interventions to control alveolar bone loss in periodontal disease.